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European Journal of Human Genetics: EJHG

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https://www.readbyqxmd.com/read/29343805/biallelic-variants-in-kif14-cause-intellectual-disability-with-microcephaly
#1
Periklis Makrythanasis, Reza Maroofian, Asbjørg Stray-Pedersen, Damir Musaev, Maha S Zaki, Iman G Mahmoud, Laila Selim, Amera Elbadawy, Shalini N Jhangiani, Zeynep H Coban Akdemir, Tomasz Gambin, Hanne S Sorte, Arvid Heiberg, Jennifer McEvoy-Venneri, Kiely N James, Valentina Stanley, Denice Belandres, Michel Guipponi, Federico A Santoni, Najmeh Ahangari, Fatemeh Tara, Mohammad Doosti, Justyna Iwaszkiewicz, Vincent Zoete, Paul Hoff Backe, Hanan Hamamy, Joseph G Gleeson, James R Lupski, Ehsan Ghayoor Karimiani, Stylianos E Antonarakis
Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p...
January 17, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29343804/compound-heterozygous-spata5-variants-in-four-families-and-functional-studies-of-spata5-deficiency
#2
Sanna Puusepp, Reka Kovacs-Nagy, Bader Alhaddad, Matthias Braunisch, Georg F Hoffmann, Urania Kotzaeridou, Lucia Lichvarova, Mailis Liiv, Christine Makowski, Merle Mandel, Thomas Meitinger, Sander Pajusalu, Richard J Rodenburg, Dzhamilja Safiulina, Tim M Strom, Inga Talvik, Annika Vaarmann, Callum Wilson, Allen Kaasik, Tobias B Haack, Katrin Õunap
Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene...
January 17, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29343803/targeted-next-generation-sequencing-in-a-young-population-with-suspected-inherited-malignant-cardiac-arrhythmias
#3
Anders Krogh Broendberg, Morten Krogh Christiansen, Jens Cosedis Nielsen, Lisbeth Noerum Pedersen, Henrik Kjaerulf Jensen
Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999-2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort...
January 17, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29335492/assessing-the-effectiveness-of-nice-criteria-for-stratifying-breast-cancer-risk-in-a-uk-cohort
#4
Lucy A Littlejohn, Jim Gibbs, Lee B Jordan, Zosia H Miedzybrodzka, Christine Bell, David Goudie, Jacqueline Dunlop, Jonathan N Berg
Breast cancer risk is a common indication for referral to clinical genetics services. UK National Institute of Health and Care Excellence (NICE) guidelines use family history (FH) to stratify by 10-year risk of breast cancer from age 40. Patients are stratified into population risk (PR, 10-year risk <3%), moderate (MR, 3-8%) and high risk (HR, >8%). Women at increased risk are offered screening at or prior to age 40. To assess the clinical effectiveness of current risk stratification, FH data were obtained for all unaffected women with a FH of breast cancer aged <50, referred to cancer genetics from 2000-2010...
January 15, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330548/shox-haploinsufficiency-presenting-with-isolated-short-long-bones-in-the-second-and-third-trimester
#5
Shwetha Ramachandrappa, Abhijit Kulkarni, Hina Gandhi, Cheryl Ellis, Renata Hutt, Lesley Roberts, Rosol Hamid, Aris Papageorghiou, Sahar Mansour
Haploinsufficiency of the transcription factor short stature homeobox (SHOX) manifests as a spectrum of clinical phenotypes, ranging from disproportionate short stature and Madelung deformity to isolated short stature. Here, we describe five infants with molecularly confirmed diagnoses of SHOX haploinsufficiency who presented in utero with short long bones during routine antenatal scanning from as early as 19 weeks gestation. Other foetal growth parameters were normal. The molecular basis of SHOX haploinsufficiency was distinct in each case...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330547/recessive-loss-of-function-pign-alleles-including-an-intragenic-deletion-with-founder-effect-in-la-r%C3%A3-union-island-in-patients-with-fryns-syndrome
#6
Jean-Luc Alessandri, Christopher T Gordon, Marie-Line Jacquemont, Nicolas Gruchy, Norbert F Ajeawung, Guillaume Benoist, Myriam Oufadem, Asma Chebil, Yannis Duffourd, Coralie Dumont, Marion Gérard, Paul Kuentz, Thibaud Jouan, Francesca Filippini, Thi Tuyet Mai Nguyen, Olivier Alibeu, Christine Bole-Feysot, Patrick Nitschké, Asma Omarjee, Duksha Ramful, Hanitra Randrianaivo, Bérénice Doray, Laurence Faivre, Jeanne Amiel, Philippe M Campeau, Julien Thevenon
Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330546/older-mothers-and-increased-impact-of-prenatal-screening-stable-livebirth-prevalence-of-trisomy-21-in-the-netherlands-for-the-period-2000-2013
#7
Maurike D de Groot-van der Mooren, Saskia Tamminga, Dick Oepkes, Michel E Weijerman, Martina C Cornel
In the Netherlands, there is no registry system regarding the livebirth prevalence of trisomy 21 (T21). In 2007, a national screening programme was introduced for all pregnant women, which may have changed the livebirth prevalence of T21. The aim of this study is to analyse trends in factors that influence livebirth prevalence of T21 and to estimate the livebirth prevalence of T21 for the period of 2000-2013. National data sets were used on the following: (1) livebirths according to maternal age and (2) prenatal testing and termination of pregnancy (ToP) following diagnosis of T21...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330545/de-novo-bk-channel-variant-causes-epilepsy-by-affecting-voltage-gating-but-not-ca2-sensitivity
#8
Xia Li, Sibylle Poschmann, Qiuyun Chen, Walid Fazeli, Nelly Jouayed Oundjian, Francesca M Snoeijen-Schouwenaars, Oliver Fricke, Erik-Jan Kamsteeg, Marjolein Willemsen, Qing Kenneth Wang
Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330544/perceptions-of-legislation-relating-to-the-sharing-of-genomic-biobank-results-with-donors-a-survey-of-bbmri-eric-biobanks
#9
Minna Brunfeldt, Harriet Teare, Sirpa Soini, Helena Kääriäinen
Biobanks accumulate huge amounts of research findings, including participants' genomic data. Increasingly this leads to biobanks receiving research results that could be of clinical significance to biobank participants. The EU Horizon 2020 Project 'Genetics Clinic of the Future' surveyed European biobanks' perceptions of the legal and regulatory requirements for communicating individual research results to donors. The goal was to gain background knowledge for possible future guidelines, especially relating to the consent process...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29330543/cugc-for-duchenne-muscular-dystrophy-dmd
#10
David J Coote, Mark R Davis, Macarena Cabrera, Merrilee Needham, Nigel G Laing, Kristen J Nowak
No abstract text is available yet for this article.
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29326429/responsible-innovation-in-human-germline-gene-editing-background-document-to-the-recommendations-of-eshg-and-eshre
#11
Guido De Wert, Björn Heindryckx, Guido Pennings, Angus Clarke, Ursula Eichenlaub-Ritter, Carla G van El, Francesca Forzano, Mariëtte Goddijn, Heidi C Howard, Dragica Radojkovic, Emmanuelle Rial-Sebbag, Wybo Dondorp, Basil C Tarlatzis, Martina C Cornel
Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29326428/human-germline-gene-editing-recommendations-of-eshg-and-eshre
#12
Guido de Wert, Guido Pennings, Angus Clarke, Ursula Eichenlaub-Ritter, Carla G van El, Francesca Forzano, Mariëtte Goddijn, Björn Heindryckx, Heidi C Howard, Dragica Radojkovic, Emmanuelle Rial-Sebbag, Basil C Tarlatzis, Martina C Cornel
Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29321672/phenotypic-interpretation-of-complex-chromosomal-rearrangements-informed-by-nucleotide-level-resolution-and-structural-organization-of-chromatin
#13
Cinthya J Zepeda-Mendoza, Alexandra Bardon, Tammy Kammin, David J Harris, Helen Cox, Claire Redin, Zehra Ordulu, Michael E Talkowski, Cynthia C Morton
Molecular characterization of balanced chromosomal abnormalities constitutes a powerful tool in understanding the pathogenic mechanisms of complex genetic disorders. Here we report a male with severe global developmental delay in the presence of a complex karyotype and normal microarray and exome studies. The subject, referred to as DGAP294, has two de novo apparently balanced translocations involving chromosomes 1 and 14, and chromosomes 4 and 10, disrupting several different transcripts of adhesion G protein-coupled receptor L2 (ADGRL2) and protocadherin 15 (PCDH15)...
January 10, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29321671/preconception-carrier-screening-for-multiple-disorders-evaluation-of-a-screening-offer-in-a-dutch-founder-population
#14
Inge B Mathijssen, Kim C A Holtkamp, Cecile P E Ottenheim, Janneke M C van Eeten-Nijman, Phillis Lakeman, Hanne Meijers-Heijboer, Merel C van Maarle, Lidewij Henneman
Technological developments have enabled carrier screening for multiple disorders. This study evaluated experiences with a preconception carrier screening offer for four recessive disorders in a Dutch founder population. Questionnaires were completed by 182 attendees pretesting and posttesting and by 137 non-attendees. Semistructured interviews were conducted with seven of the eight carrier couples. Attendees were mainly informed about the existence of screening by friends/colleagues (49%) and family members (44%)...
January 10, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29321670/clinical-and-experimental-evidence-suggest-a-link-between-kif7-and-c5orf42-related-ciliopathies-through-sonic-hedgehog-signaling
#15
Reza Asadollahi, Justin E Strauss, Martin Zenker, Oliver Beuing, Simon Edvardson, Orly Elpeleg, Tim M Strom, Pascal Joset, Dunja Niedrist, Christine Otte, Beatrice Oneda, Paranchai Boonsawat, Silvia Azzarello-Burri, Deborah Bartholdi, Michael Papik, Markus Zweier, Cordula Haas, Arif B Ekici, Alessandra Baumer, Eugen Boltshauser, Katharina Steindl, Michael Nothnagel, Albert Schinzel, Esther T Stoeckli, Anita Rauch
Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies...
January 10, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29321669/phenotypic-characteristics-of-colorectal-cancer-in-brca1-2-mutation-carriers
#16
Albert Grinshpun, Naama Halpern, Roy Zvi Granit, Ayala Hubert, Tamar Hamburger, Yael Laitman, Einat Shacham-Shmueli, Yehudit Peerless, Eitan Friedman, Tamar Peretz
Mutations in the BRCA1/2 genes were recently shown to be associated with an increased risk for colorectal cancer. We characterized the largest cohort available of BRCA1/2 mutation carriers with colorectal cancer. We analyzed 32 patients with lower gastrointestinal cancers and germline BRCA1/2 mutations from two large academic hospital registries; 91% of patients were of Ashkenazi ancestry, 78% were women, and 62.5% were carriers of BRCA1 gene mutations. A high percentage of colorectal tumors (34.5%) had a mucinous histology and were located atypically in the left colon...
January 10, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29302048/diagnostic-challenges-in-a-child-with-early-onset-desmoplastic-medulloblastoma-and-homozygous-variants-in-msh2-and-msh6
#17
Julia Taeubner, Katharina Wimmer, Martine Muleris, Olivier Lascols, Chrystelle Colas, Christine Fauth, Triantafyllia Brozou, Joerg Felsberg, Jasmin Riemer, Michael Gombert, Sebastian Ginzel, Jessica I Hoell, Arndt Borkhardt, Michaela Kuhlen
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR) genes. The spectrum of CMMRD-associated tumours is very broad and many CMMRD patients additionally display signposting non-neoplastic features, most frequently café-au-lait macules and other pigmentation alterations. We report on a 13-month-old girl suspected of having CMMRD due to a desmoplastic medulloblastoma and a striking skin pigmentation that included multiple café-au-lait macules, hypopigmented areas and Mongolian spots...
January 4, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29302047/functional-and-association-analysis-of-an-amerindian-derived-population-specific-p-thr280met-variant-in-rbpjl-a-component-of-the-ptf1-complex
#18
Anup K Nair, Jeff R Sutherland, Michael Traurig, Paolo Piaggi, Peng Chen, Sayuko Kobes, Robert L Hanson, Clifton Bogardus, Leslie J Baier
PTF1 complex is critical for pancreatic development and maintenance of adult exocrine pancreas. As a part of our ongoing studies to identify genetic variation that contributes to type 2 diabetes (T2D) in American Indians, we analyzed variation in genes that form this complex, namely PTF1A, RBPJ, and its paralogue RBPJL. A c.839C>T (p.(Thr280Met)) variant (rs200998587:C>T, risk allele frequency = 0.03) in RBPJL, identified only in Amerindian-derived populations, associated with T2D (OR = 1.60[1...
January 4, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29289958/regulatory-variants-of-foxg1-in-the-context-of-its-topological-domain-organisation
#19
Mana M Mehrjouy, Ana Carolina S Fonseca, Nadja Ehmke, Giorgio Paskulin, Antonio Novelli, Francesco Benedicenti, Maria Antonietta Mencarelli, Alessandra Renieri, Tiffany Busa, Chantal Missirian, Claus Hansen, Kikue Terada Abe, Carlos Eduardo Speck-Martins, Angela M Vianna-Morgante, Mads Bak, Niels Tommerup
FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD...
December 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29255276/charge-syndrome-a-recurrent-hotspot-of-mutations-in-chd7-ivs25-analyzed-by-bioinformatic-tools-and-minigene-assays
#20
Marine Legendre, Montserrat Rodriguez-Ballesteros, Massimiliano Rossi, Véronique Abadie, Jeanne Amiel, Nicole Revencu, Patricia Blanchet, Frédéric Brioude, Marie-Ange Delrue, Yassamine Doubaj, Abdelaziz Sefiani, Christine Francannet, Muriel Holder-Espinasse, Pierre-Simon Jouk, Sophie Julia, Judith Melki, Sébastien Mur, Sophie Naudion, Jennifer Fabre-Teste, Tiffany Busa, Stephen Stamm, Stanislas Lyonnet, Tania Attie-Bitach, Alain Kitzis, Brigitte Gilbert-Dussardier, Frédéric Bilan
CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site...
December 18, 2017: European Journal of Human Genetics: EJHG
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